Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder characterized by loss of lower motor neurons and skeletal muscle atrophy. SBMA is caused by CAG expansions (>38 repeats) encoding a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. The disease fully manifests in males, as they have high levels of androgens in the serum. PolyQ-AR is converted to a toxic species upon binding to androgens, testosterone and dihydrotestosterone (DHT). We propose to identify the genes involved in regulating polyQ-AR-mediated toxicity and advance our understanding about the molecular mechanisms underlying SBMA pathogenesis. The main objective of current R21 application is to determine that transcriptional co-regulators of AR mediate the toxic gain-of-function (GOF) of polyQ-AR. We hypothesize that two AR transcription co-regulators, namely protein arginine methyltransferase 6 (PRMT6) and lysine demethylase 1 (LSD1), synergistically cooperate to enhance the toxic GOF of polyQ-AR by changing its transcriptional activity. Our hypothesis is based on our observations that post- translational modifications (phosphorylation and methylation)) of AR are important determinant of the toxicity. We will utilize well-characterized mouse models of SBMA (transgenic AR100Q and knock-in AR113Q mice) that show hormone- and glutamine length?dependent neuromuscular weakness, muscle pathology, and early death. SBMA transgenic and knock-in mice represent good models to study disease pathogenesis and to test pharmacologic intervention. We propose to determine how co-regulators of polyQ-AR function in SBMA. We expect to determine how AR function is regulated in skeletal muscle and dysregulated in SBMA.